JPH07224077A - Production of 9-(z)-retinoic acid - Google Patents

Abstract

PURPOSE: To obtain the subject substance from a mother liquor of a triarylphosphonium salt which has been discarded heretofore, by extracting the mother liquor with water, concentrating the resultant extract by evaporation and subjecting the resultant isolated product to a reaction or a treatment under spcific conditions.

CONSTITUTION: A mother liquior of 15C triarylphosphonium salt represented by formula I (wherein R¹-R³ are each aryl; and X is halogen or HSO₄) is extracted with water and the obtained aq. phase is evaporatively concentrated and the content of a 9-(Z)-15C triarylphosphonium salt is increased by dissolving an oily 15C triarylphosphonium salt in a slight amt. of a lower alcohol under heating and separating all of (E)-15C triarylphosphonium salts precipitated by cooling the resulting soln. The compd. represented by formula I enriched in the content of the 9-(Z)-isomer is subjected to a Witting reaction with an alkyl β-formylcrotonate represented by formula II (wherein R⁴ is 1-4C alkyl) in the presence of alkali (earth) metal hydroxide or ammonia in a solvent. The obtained product is saponified in a 3-9C alkanol and precipitated as a crystal optionally by using methanol to obtain the objective substance.

COPYRIGHT: (C)1995,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 9- (Z) -retinoic acid.

[0002]

9- (Z) -retinoic acid is a physiologically important substance (Nature 355 (1992) 359-36).
(See page 1). The substance is a nuclear retinoic acid receptor RXRα that is activated by direct ligand interaction.
Has a high binding affinity for. As a result of this interaction, an altered gene phenotype is observed, which allows a wide range of effects on cell processing.

The task of the present invention was to develop an advantageous process for the preparation of 9- (Z) -retinoic acid, since no practical process for the preparation of 9- (Z) -retinoic acid is known.

The most frequently used retinoic acid isomers to date, all- (E) -retinoic acid, are preferably β-ionylidene-triphenylphosphonium salts (C ₁₅ -triphenylphosphonium salts) and β-formyl-. Obtained by Wittig reaction with crotonic acid ester. The subsequent separation of the obtained double bond isomers is possible only by using the preparative chromatography method in a significantly expensive manner.

C ₁₅ -triphenylphosphonium salts (eg Angew. Chem. 77 (1965) 277-360 H, which are required for the industrial synthesis of vitamin A and the production of other vitamin A derivatives such as retinal and retinoic acid. . Po
mmer in the case of production of other things reference), the mother liquor formed after the separation of the target product, this is the mother liquor in the total (E) -C ₁₅ -
In addition to the triphenylphosphonium salt, the 9- (Z) -isomer is 10-based on the total C ₁₅ -triphenylphosphonium salt.
It is contained in an amount of 60% by weight, in particular 30 to 55% by weight. Direct use of this mother liquor for the production of 9- (Z) -retinoic acid is not possible without significant difficulty.

[0006]

The object of the present invention is therefore to develop a process whereby the desired 9- (Z) -retinoic acid can be prepared simply from the mother liquor of the C ₁₅ -triphenylphosphonium salt preparation. Met.

[0007]

The object of the present invention is 9-
The general formula I of (Z) -retinoic acid in an organic solvent:

[0008]

[Chemical 3]

[Wherein R ^{1 to} R ³ represent an aryl group, preferably a phenyl group, and X represents a halogen atom or (HSO ₄ ).
In the method for producing a C ₁₅ -triphenylphosphonium salt represented by the formula from a mother liquor of industrial production, A. In a C ₁₅ -triarylphosphonium salt isolated from the mother liquor by extraction with water and evaporation of the aqueous phase,
The content of the-(Z) -C ₁₅ -triarylphosphonium salt was determined by dissolving the oily C ₁₅ -triarylphosphonium salt mixture under heating in as little lower alcohol as possible, preferably in isopropanol, and cooling. Enriched by separating out all the (E) -C ₁₅ -triarylphosphonium salts that emerge, B. The resulting 9- (Z) -isomer enriched formula I
The C ₁₅ - in the presence of a base conventionally used a triaryl phosphonium salts during the Wittig reaction, in particular an alkali metal - or alkaline earth metal hydroxides, alkali metal - or alkaline earth metal amide, an alkali metal carbonate In the presence of salt or ammonia in a solvent suitable for the Wittig reaction, a compound of general formula II:

[0010]

[Chemical 4]

[Wherein R ⁴ represents a C ₁ -C ₄ -alkyl group], which is reacted with an alkyl ester of β-formyl maltotonate to give C.I. The above-mentioned retinoic acid ester mixture obtained by the usual post-treatment for the Wittig reaction was used as C _{3 to} C ₉ −.
9-obtained by saponification in an alkanol, preferably propanol or butanol, in particular isoptanol.
The (Z) -retinoic acid is precipitated as crystals from alkanolic, preferably propanolic or butanolic solutions, optionally by addition of methanol, in which case the total (E) -retinoic acid formed and other unknowns are formed. The retinoic acid isomer is a process characterized by remaining in the alkanolic solution.

[0012]

In particular, pure 9- (Z) -retinoic acid is obtained by reacting the resulting 9- (Z) -retinoic acid with butanol /
It is obtained when recrystallized from a methanol mixture, especially an isobutanol / methanol mixture.

Particularly preferably, the present invention is
The content of 9- (Z) -C ₁₅ -triarylphosphonium salt is from the mother liquor of the C ₁₅ -triarylphosphonium salt production, a) water is added to the mother liquor, and the organic phase is separated, b) the aqueous phase is carefully E) concentrated under different conditions, c) the oil thus obtained is dissolved in as little isopropanol as possible under heating, and d) a total (E) -C ₁₅ -triarylphosphonium which crystallizes on cooling. This is done if the salts are separated off, and e) isolated and enriched by evaporative concentration of the resulting isopropanolic solution under elaborate conditions.

The C ₁₅ -triarylphosphonium salts are prepared in a manner known per se, usually in solvents such as toluene, acetonitrile, xylene, decalin, methylene chloride, methyl-t-butyl ether, water and alkanols.

The mother liquor required for the process according to the invention is therefore one of the abovementioned solvents or a mixture of solvents, triphenylphosphine oxide, halogenated hydrocarbons or sulfuric acids and C ₁₅ -hydrocarbons and hydroacids or sulfuric acids. The triarylphosphonium salt of

The mother liquor contains 10 to 60%, in particular 30 to 55%, of the 9- (Z) -isomer, based on the amount of total C ₁₅ -triarylphosphonium salt, depending on the reaction conditions. C ₁₅ from the mother liquor - triarylphosphonium salt is extracted with water, and the aqueous phase is concentrated by evaporation elaborate conditions. The oil thus obtained has a salt concentration of 3
0-70% by weight, especially 40-60% by weight, especially 45-5
At 5% by weight it is absorbed in some amount of lower alkanol, preferably isopropanol. The solution obtained is subsequently left at a temperature of −50 to 25 ° C., in particular −30 to 0 ° C., in which case the total (E) -triarylphosphonium salt is crystallized and separated in this way. You can After this enrichment of 9- (Z) -C ₁₅ -salt in mother liquor,
- (Z) -C ₁₅ - triphenylphosphonium salt and the total (E) -C ₁₅ - the ratio of the triphenyl phosphonium salt,
It is about 1: 1 to 50: 1. According to the example, about 15:
A 90: 6 ratio corresponding to 1 was achieved. 9- (Z)-
A further enrichment of the isomers are possible dynamics governing the Wittig reaction and subsequently as a basis, the total was also residual because it (E) - isomer, 9- (Z) -C ₁₅ -
This is because the Wittig reaction occurs significantly faster than the triarylphosphonium salt. Thus, if the C ₁₅ -triarylphosphonium salt mixture reacts during the Wittig reaction with an amount of the aldehyde compound which corresponds to the amount still contained in the total (E) -C ₁₅ -salt, the acidity of the reaction mixture The subsequent workup isolates the 9- (Z) -C ₁₅ -triarylphosphonium salt based on kinetic differences.

The process according to the invention for producing 9- (Z) -retinoic acid is such that during reaction step B the 9- (Z)-
The isomer-enriched C ₁₅ -triarylphosphonium salts of the general formula I, in particular in the presence of the bases customarily used for Wittig reactions, in particular alkali metal or alkaline earth metal hydroxides, alkali metal Dimethylformamide as solvent in the presence of carbonates or ammonia, alkanol-dimethylformamide mixtures, alkanol-water mixtures, 1,4-dioxane, water or N-methyl-pyrrolidone, preferably β of the general formula II in dimethylformamide. There are additional advantages when reacting with formyl-crotonic acid alkyl esters. Usually, the Wittig reaction is carried out in a manner known per se at a temperature of -30 to about +30.
C., in particular -10.degree. C. to + 10.degree. C., in particular about 0.degree. In this case the starting compounds of both the C ₁₅ -triarylphosphonium salt and the β-formyl-crotonic acid may be charged in a solvent and a base may be added to this solution, or alternatively the C ₁₅ -triaryl is added. The solution of the phosphonium salt is charged, the base is added and only then is β-formyl-
A solution of crotonic acid alkyl ester may be added.

To carry out a particularly advantageous form of the Wittig reaction, lithium hydroxide is suspended in dimethylformamide (DMF) and cooled to 0.degree. To the cooled suspension is first slowly added a solution of the C ₁₅ -triarylphosphonium salt in DMF and then slowly a solution of the β-formyl-crotonate ester in DMF. Temperature +10 to -9 ° C, especially +5 to -5
After stirring for 2 to 10 hours, in particular 3 to 5 hours at 0 ° C, in particular +2 to -2 ° C, ice water is added to the reaction mixture. Furthermore, the water / DMF phase is extracted, for example with a heptane / acetic acid ethyl ester mixture.

The organic phase is washed with water and freed from the solvent at about 40 ° C.

In this case, the base, in particular lithium hydroxide, is used in total in an amount of 2 to 6 mol, in particular 3 to 5 mol, per mol of C ₁₅ -triarylphosphonium salt.

The solvent, especially DMF, is usually used in an amount of 2 to 8 liters (l), in particular 3 to 6 liters, per mole of C ₁₅ -triarylphosphonium salt.

The extractant used is preferably heptane or a mixture of heptane and ethyl acetate. However, all other organic solvents which are immiscible with water, such as ethers, aliphatic hydrocarbons, halogenated aromatic hydrocarbons, can also be used for the extraction of the retinoic acid alkyl ester isomer mixture.

Solvents, in particular DMF and alkanols, remain well in the aqueous phase during this extraction, and the triphenylphosphine oxide formed during the Wittig reaction remains well in the aqueous phase.

When a C ₁₅ -triarylphosphonium halogenide is used, the Wittig reaction with an alkyl β-formyl mrotonic acid ester of the general formula II is carried out by C reaction.
In a 1,2-epoxy-alkane having 3 to 6 atoms,
It has proved to be advantageous to work in 1,2-epoxy-butane or 1,2-epoxyhexane and without the use of one of the bases customarily used in Wittig reactions. There is. In this case 1,
2-epoxy - alkanes, C ₁₅ - triaryl phosphonium halogenide halogenated hydrocarbons 2- halogens nido - C ₁₅ alkanol and correspondingly - triaryl -. Phosphorane separate with formation of (J. Buddrus, Angew Che
m. 80 (1968), pp. 35-36). Furthermore, these 2-halogen-alkanols and the corresponding C ₁₅ -triaryl-phosphoranes are converted into the corresponding retinoic acid alkyl esters by reaction with the β-formyl mrotonic acid alkyl esters of the general formula II. The 1,2-epoxy-alkane acts as a solvent as well as a base during this reaction.

To carry out this process variant, the C ₁₅ -triarylphosphonium halogenide and the β-formyl crotonic acid ester are suspended in a 1,2-epoxy-alkane, the suspension being gradually warmed. About 35-65 ° C, especially 5
Heated to 5 to 65 ° C and still 2 to 5 at this temperature
It is stirred for 24 hours, in particular 4 to 16 hours. After the Wittig reaction is complete, the epoxy alkane is distilled off from the reaction mixture under careful conditions.

1,2-Epoxy-alkanes, like other solvents, are C ₁₅ -triarylphosphonium halides 1.
It is used in an amount of about 2 to 8 l, in particular 3 to 6 l, per mole.

Work-up of the reaction mixture is carried out essentially as described above for the Wittig reaction in another solvent.

A further great advantage of the process according to the invention is that during reaction stage C: a) the oily retinoic acid alkyl ester obtained is dissolved in propanol or butanol, and b) 10-80 wt. %, In particular 15-60% by weight, in particular 20-30% by weight, are saponified with an aqueous solution of an alkali metal or alkaline earth metal hydroxide, in particular alkali metal hydroxide, c) the inorganic acid is cooled. Retinoic acid is liberated by addition to the alkaline reaction mixture prepared, and d) when 9- (Z) -retinoic acid precipitates as crystals by addition of methanol to the propanolic or butanolic solution. To be achieved.

Surprisingly, no adverse effect on the isomer ratio occurs in the case of the abovementioned method of ester separation. When C ₃ -C ₉ -alkanols, in particular propanol and butanol, especially isobutanol, are used as solvents for the ester separation, 9- (Z) -retinoic acid is obtained especially by addition of a lower alkanol, especially methanol. It can preferably be precipitated in the form of bright orange crystals, while all (E) -retinoic acid or other retinoic acid isomers are contained in the solution. Optionally 9- in the alkanol
The concentration of (Z) -retinoic acid ester should be adjusted during saponification to such an extent that crystallization of 9- (Z) -retinoic acid from the reaction mixture can be achieved without addition of methanol. You can

Using the process according to the invention, 9- (Z) -retinoic acid can be obtained for the first time in a simple manner and without the use of expensive chromatographic purification steps in the final stage. It is particularly advantageous that the mother liquor produced during the large-scale industrial production of C ₁₅ -triarylphosphonium salts, which until now had to be disposed of, can be utilized. According to the invention, 9-
The enrichment of the (Z) -C ₁₅ -triarylphosphonium salt is
It is relatively easy to carry out, which allows
The problem-free isolation of 9- (Z) -retinoic acid is made possible in a special solvent system at the final stage of the process according to the invention.

Next, the present invention will be described in detail with reference to examples.

The following conditions were selected for the HPLC analysis: a) C ₁₅ -triphenylphosphonium salt; Nucleosyl 120, 7 μm, RP-18, 1 ml /
Min, 220 nm, methanol / water = 7: 3 + 0.04%
Cetyl ammonium bromide, pH = 2.0 b) Retinoic acid; Lichrosorb, 5μ
m, RP-18, 1.2 ml / min, 352 nm, methanol / water / acetic acid = 80: 20: 0.5.

[0033]

【Example】

Example 1 Preparation of 9- (Z) -retinoic acid 9- (Z) -C ₁₅ - triphenylphosphonium salt enriched heptane / isopropanol in 3-methyl-5-
(2,6,6-trimethyl-1-cyclohexene-1-
Yl) -2,4-pentadienyl-triphenylphosphonium hydrogensulfate (C ₁₅ -triphenylphosphonium sulphate) in the mother liquor 1 1 of water 25
0 ml was added and mixed vigorously. After separation of the organic phase, the aqueous solution was completely evaporated at 90 ° C. in a rotary evaporator. 91.8 g of a light brown oil are obtained, which oil is
According to C analysis, up to about 38% consist of 9- (Z) -C ₁₅ -triphenylphosphonium sulphate and 53
Up to%, it consisted of all (E) -C ₁₅ -triphenylphosphonium sulphate. The oil was taken up in 120 ml of Isopropal, a solution of about 50% by weight being obtained. Subsequently, the solution was left in the refrigerator overnight, the precipitated crystals were filtered off and the solution was concentrated by evaporation in a rotary evaporator. 42.2 g of a light brown oil are obtained, which by HPLC analysis is about 65.8%.
Until 9- (Z) -C ₁₅ - consists triphenylphosphonium hydrogensulfate sulfate, and up to 19% total (E) -C ₁₅ - consisted triphenylphosphonium hydrogensulfate sulfate.

B. Wittig Reaction with β-Formyl Mrotonic Acid Methyl Ester 9 g (0.37 mol) of LiOH were suspended in 100 ml of dimethylformamide (DMF) and cooled to 0 ° C. under N ₂ protective gas atmosphere. Subsequently, A. 39.6 g (0.0704 mol) of a solution of the C ₁₅ -triphenylphosphonium salt obtained according to was added dropwise to the LiOH suspension at 0 ° C. for 30 minutes. Continue to DM
A solution of 14.5 g (0.113 mol) of β-formyl crotonic acid methyl ester in 70 ml of F was added over 30 minutes.

After the reaction mixture was stirred at 0 ° C. for 4 hours, 400 ml of ice water was added. Further, the water / DMF phase was mixed with 180 ml of a heptane / acetic acid ethyl ester (2/1) mixture.
It was extracted 3 times with. The organic phase obtained is washed twice more with 100 ml of water each time and then concentrated by evaporation in a rotary evaporator, giving 17.85 g of a brown oil.

C. Isolation of 9- (Z) -retinoic acid B. Retinoic acid ester mixture 1 obtained by
Absorb 7.85 g in 50 ml isobutanol and 2
12.5 g of a 5% by weight aqueous NaOH solution are added and the reaction mixture is first kept at 80 ° C. for 75 minutes and a further 60%.
It was cooled to 0 ° C. and 38 ml of a 10% by weight aqueous sulfuric acid solution were added. After separation of the phases, the isobutanol phase was mixed with methanol 40
ml was added, in which case 9- (Z) -retinoic acid crystallized out immediately. 50 ml of methanol (-
It was washed twice at 30 ° C). 4 g of 9- (Z) -retinoic acid were obtained. This, C ₁₅ - are contained in the mother liquor of the salt product 9- (Z) -C ₁₅ - corresponds to 32% yield based on phosphonium hydrogenphosphate sulfate - triphenyl.

The alcoholic mother liquor (13.5 g) obtained after isolation of 9- (Z) -retinoic acid is still up to 35% according to HPLC analysis, total (E) -retinoic acid, 9-.
It consisted of 17.2% (Z) -retinoic acid and 34% of the unknown retinoic acid isomer.

D. Recrystallization of 9- (Z) -retinoic acid A. ~ C. 5.2 g (purity 94.3%) of 9- (Z) -retinoic acid obtained in the same manner as in (1) were stirred in 80 ml of isobutanol / methanol mixture (1/1) at 80 ° C. for 10 minutes. Subsequently, it was cooled to 0 ° C. 9-in an hour
(Z) -retinoic acid crystallized out and was filtered off, methanol 5
It was washed with 0 ml (-30 ° C). 4.0 g of 9- (Z) -retinoic acid was obtained with a purity of 99.5%.

Example 2 A. 9- (Z) -C ₁₅ - triphenylphosphonium halogenide of enrichment heptane / isopropanol in 3-methyl-5-
(2,6,6) -Trimethyl-1-cyclohexene-1
-Yl) -2,4-pentadienyl-triphenylphosphonium chloride To 1 liter of mother liquor was added 300 ml of water and mixed vigorously. After separation of the organic phase, the aqueous solution was completely concentrated by evaporation at 80 ° C. in a rotary evaporator. 102 g of a light brown oil are obtained, which according to HPLC analysis comprise up to about 42% 9- (Z) -C ₁₅ -triphenylphosphonium chloride and up to 44% total (E).
-C ₁₅ - consisted triphenyl phosphonium chloride. The oil was taken up in 150 ml of Isopropal, a solution of about 50% by weight being obtained. Subsequently, the solution was left overnight in the refrigerator, all the crystallized (E) -C ₁₅ -triphenylphosphonium chloride was filtered off and the solution was concentrated by evaporation in a rotary evaporator. A light brown oil was obtained which by HPLC analysis consisted of up to about 63% 9- (Z) -C ₁₅ -triphenylphosphonium chloride.

B. Wittig Reaction in 1,2-Epoxy-Butane Example 2A. 50.05 g (0.1 mol) of the C ₁₅ -triphenylphosphonium chloride obtained according to (1) was suspended in 500 ml of 1,2-epoxy-butane and added to this suspension.
Β-formyl-crotonic acid methyl ester 14.1 at ℃
g (0.11 mol) was added and the mixture was further heated to a reflux temperature of 65 ° C. for 1 hour and subsequently heated at reflux for another 12 hours. Thereafter, the excess 1,2-epoxy-butane was distilled off at 40 ° C./150-200 mbar, and the residue was 250 ml of a hexane / acetic acid ethyl ester mixture (1: 1) and 250 ml of water cooled to 5 ° C.
Was added and extracted. The obtained organic phase is water 100 times
It was washed twice more with ml and concentrated further by evaporation at 30 ° C./20 mbar, giving 19.2 g of a brown oil. The 9- (Z) -content in the retinoic acid methyl ester mixture thus obtained was 37-41% by weight according to HPLC analysis.

C. Isolation and purification of 9- (Z) -retinoic acid was carried out as in Examples 1C and 1D.

Example 3 Wittig Reaction in 1,2-Epoxy-Hexane Example 2A. 25 g (0.046 mol) of C ₁₅ -triphenylphosphonium bromide obtained in the same manner as described above was added to 9.6 g (0.075 mol) of β-formyl-crotonic acid methyl ester in 250 ml of 1,2-epoxy-hexane. Charged together, the mixture was heated to 62 ° C. for 2 hours and stirred at this temperature for a further 10 hours. Subsequently, an excess amount of 1,2-epoxy-hexane (boiling point 116-120
C.) at 60.degree. C./50-100 mbar, and to the residue 100 ml heptane, 100 ethyl acetate.
2 wt% aqueous caustic soda liquor cooled to 5 ml and 5 ° C
00 ml was added and extracted. The aqueous phase obtained is treated with a heptane / acetic acid methyl ester mixture (2: 1), 150 ml each.
It was extracted twice. The combined organic phases were washed three times with water and concentrated further by evaporation at 30 ° C./20 mbar. 8.5 g of a brownish oil were obtained, which oil was converted into pure 9- (Z) -retinoic acid as in Examples 1C and 1D.

Claims (1)

[Claims] 1. 9- (Z) -retinoic acid in an organic solvent having the general formula I: [Wherein R ^{1 to} R ³ represent an aryl group, and X represents a halogen atom or a group (HSO ₄ )], and a method for producing the C ₁₅ -triarylphosphonium salt from a mother liquor for industrial production, A. In a C ₁₅ -triarylphosphonium salt isolated from the mother liquor by extraction with water and evaporation of the aqueous phase,
- the content of triaryl phosphonium salts, oily _{C 15 - - (Z) -C} 15 total dissolved triaryl phosphonium salt mixture lowest possible lower alcohol under heating, and crystallizing by cooling (E) -C ₁₅ - enriched by separating the triaryl phosphonium salts, B. The resulting 9- (Z) -isomer enriched formula I
C ₁₅ -triarylphosphonium salt of
Alternatively, in the presence of an alkaline earth metal hydroxide, an alkali metal or alkaline earth metal amide, an alkali metal carbonate or ammonia, in a solvent suitable for the Wittig reaction, a compound of the general formula II: [Wherein R ⁴ represents a C ₁ -C ₄ -alkyl group] and reacted with a β-formyl mrotonic acid alkyl ester, and C.I. The above-mentioned retinoic acid ester mixture obtained during the usual work-up for the Wittig reaction is saponified in a C ₃ -C ₉ -alkanol and the 9- (Z) -retinoic acid obtained is extracted from an alkanolic solution. In some cases, it was precipitated as crystals by addition of methanol, in which case all (E) -retinoic acid formed and other unknown retinoic acid isomers remained in the alkanolic solution. (Z) -Method for producing retinoic acid.